Internalizing psychopathologies (IPs) involving depression and anxiety are among the most prevalent, costly and disabling illnesses. Treatments for IPs are available but the extent to which individual patients respond is quite heterogeneous. Little information exists, particularly in the biological domain, which helps to explain individual differences in treatment response. The NIMH's Research Domain Criteria (RDoC) project may solve this problem by encouraging innovative research beyond certain categorical disorders and their associated symptoms, towards broader, core (RDoC) constructs related to brain pathophysiology, and that are shared across disorders. IPs share similar patterns of dysfunction within the Fronto-Limbic Affect Regulation and Emotional Salience (FLARES) brain circuit, and two commonly used, 'gold standard' treatments - selective serotonin reuptake inhibitors (SSRIs) and cognitive behavioral therapies (CBTs) - are equally effective for both anxiety and depressive disorders, and appear to change brain activity in the same areas within the FLARES circuit. The overarching goal of the proposed project is delineate what are common versus specific FLARE brain targets for SSRI and CBT and identify specific aspects of FLARE dysfunction that might better predict response to both and to a specific modality of treatment. The proposed experiments integrate emotion and its interaction with cognition across several stages of emotional experience, encompassing studies that probe sensitivity to acute and potential threat and automatic and volitional forms of affect regulation in relation to the FLARES brain network. These experiments will generate data on the negative valence systems (NVS) RDoC domain for multiple layers of analysis (fMRI and EEG for neural circuits, skin conductance and startle response for physiology, performance and self-reports for behavior). We propose to enroll 200 patients presenting to our Mood and Anxiety Disorders Program seeking treatment for disabling 'anxiety, worry, depressed mood' (IP,s including those characterized as Not Otherwise Specified) and randomize them to a 12-week course of SSRI or CBT. Dimensional, transdiagnostic NVS constructs, including FLARES function, will be measured before and after each treatment. Specifically, the project will examine 2 Specific Aims: 1) Where and how do SSRI and CBT treatments exert their effects on NVS constructs?; and 2) Which NVS construct can predict the likelihood of success from SSRI and CBT treatment? Such findings can be used to guide the right patients to the right treatments with the highest likelihood of success. They also elucidate a pathophysiologically-driven mechanistic model of where and how treatments work in the brain and thus hasten the development of new treatments that target the underlying pathophysiology across internalizing conditions.